Abstract
Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Monogenic diabetes constitutes less than 5% of diabetes cases, of which the two main forms affect either newborns (NDM) or young adults (MODY)[1]
MLKLG316D compromises necroptotic effector activity We examined if MLKLG316D could function as an effector of necroptotic cell death in cultured cell lines
In addition to the previously reported P33T PDX1 mutation with incomplete penetrance, we found a very rare mutation in the key necroptosis protein, Mixed Lineage Kinase Domain-Like (MLKL), present in the affected individuals only
Summary
Monogenic diabetes constitutes less than 5% of diabetes cases, of which the two main forms affect either newborns (NDM) or young adults (MODY)[1]. MODY is inherited in an autosomal dominant mode, and despite being described as monogenic, it is not fully penetrant[2]. PDX1 is a transcription factor that regulates expression of key pancreatic genes, including those encoding insulin, Additional environmental or genetic factors are clearly acting alongside PDX1 mutations in the etiology of MODY. In support of this idea, the selective, inducible inhibition of IKK/NF-κB signaling in pancreatic β-cells could induce bona fide diabetes in pre-diabetic adult Pdx1+/− mice[12]
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